JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
3, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
EDITORIAL COMMENT
Beta-Blockers in Asymptomatic
Coronary Artery Disease
No Benefit or No Evidence?*
Philippe Gabriel Steg, MD,yzx Ranil De Silva, PHDxjj
T he benefit of beta-blockers in the manage-
ment of patients with heart failure and left
ventricular dysfunction has been incontro-
vertibly established in multiple contemporary ran-
domized clinical trials (1–5). The recommendation
for use of beta-blockers after acute myocardial in-
farction (MI) is mainly based on studies (6–8) that
predate routine implementation of a contemporary
strategy of early reperfusion and modern medical
therapy, although some observational data suggest
that beta-blocker therapy may be associated with
reduced long-term mortality after early percutaneous
coronary intervention for acute MI (9,10).
In stable coronary artery disease (CAD), there is
solid evidence to show that beta-blockers effectively
relieve anginal symptoms and improve myocardial
ischemia (11), and are therefore recommended as
first-line agents for symptom relief in both U.S. (12)
and European (13) guidelines. However, the evi-
dence base for the use of beta-blockers to improve
prognosis in asymptomatic patients, who represent
w80% of the stable CAD population (14), is less robust
and not supported by data from an appropriately
* Editorials published in the Journal of the American College of Cardiology
reflect the views of the authors and do not necessarily represent the
views of JACC or the American College of Cardiology.
From the yDépartement Hospitalo-Universitaire FIRE, Hôpital Bichat,
AP-HP, and Université Paris-Diderot, Paris, France; zINSERM U-1148,
Paris, France; xNational Heart and Lung Institute, Imperial College Lon-
don, United Kingdom; and the jjNIHR Cardiovascular Biomedical
Research Unit, Royal Brompton and Harefield NHS Foundation Trust,
London, United Kingdom. Dr. Steg has received research grants from
Sanofi and Servier (to INSERM U-1148); personal fees from Amarin,
AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers-Squibb, Daiichi-
Sankyo, GlaxoSmithKline, Janssen, Eli Lilly, Medtronic, Merck-Sharpe-
Dohme, Novartis, Otsuka, Pfizer, Roche, The Medicines Company,
Sanofi, Servier, and Vivus; and is a stockholder in Aterovax. Dr. De Silva
has reported that he has no relationships relevant to the contents of this
paper to disclose.
VOL. 64, NO.
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2014.04.043
powered randomized trial. A recent report from the
REACH registry has examined the benefit of beta-
blockers in patients with stable CAD (15). In that anal-
ysis of 21,860 patients, beta-blocker usage was not
associated with a reduced rate of cardiovascular death,
nonfatal MI, nonfatal stroke, hospitalization for an
atherothrombotic event, or revascularization, even
in patients with previous MI. These data challenge
the extrapolation of the benefits of beta-blockade
observed in patients with heart failure or left ventric-
ular dysfunction to all patients with stable CAD.
SEE PAGE 247
In this issue of the Journal, Andersson et al. (16)
conducted an important, rigorous analysis of the Kai-
ser Permanente health records database. They
observed a modest benefit of beta-blockade in patients
with stable CAD. There was a clear interaction between
a prior history of MI and treatment effect, with benefits
confined to those patients with a history of prior
MI. Although these data are informative, there are a
number of issues inherent to the study design, war-
ranting consideration when interpreting the results.
Key clinical parameters, such as the presence and
severity of anginal symptoms, ischemic burden, left
ventricular function, and importantly, the type and
dose of beta-blocker therapy, were unavailable.
For beta-blocker therapy to confer clinical benefit,
significant pharmacological beta-blockade is likely
required, although it is well known that full
beta-blockade is rarely achieved in routine clinical
practice (15). The study population comprised
approximately 80% of acute coronary syndrome
(ACS) patients, while the remainder consisted of pa-
tients referred for elective revascularization pro-
cedures, which would exclude patients with incident,
stable CAD who may be managed medically without
revascularization. Therefore, the results may be in
254 Steg and De Silva JACC VOL. 64, NO. 3, 2014

Beta-Blockers in Asymptomatic CAD JULY 22, 2014:253–5

part attributable to insufficient power to detect a
benefit of beta-blockade in stable CAD patients
without previous MI, and of uncertain relevance to
the broader population of stable CAD patients not
captured in the current analysis.
Despite careful attempts by the authors to adjust
for potential confounders, interpretation of the cur-
rent findings needs to be tempered by the weak-
nesses inherent to observational studies, including
unmeasured confounders, nonuniformity of patient
inclusion criteria and event adjudication, imbal-
anced patient groups, and the retrospective ascer-
tainment of the study cohort, which necessitates
“on-treatment” rather than “intention-to-treat” ana-
lyses. The assumption that patients are adherent
to prescribed medication on the basis of filling of
prescriptions is also a potential weakness (17). That
said, both the REACH (15) and Kaiser Permanente
data are consistent with lack of demonstrable prog-
nostic benefit from beta-blocker therapy in a number
of settings of stable cardiovascular disease (18,19).
Beta-blockers may benefit patients with stable CAD
through both anti-ischemic and antiarrhythmic ef-
fects. A major mechanism of action of beta-blockers is
reduction of heart rate, which is thought to be a
determinant of clinical outcome and cardiovascular
disease progression (20). The SIGNIFY trial is testing
whether ivabradine, an I f current channel blocker that
causes selective heart rate reduction without altering
blood pressure, provides clinical benefits in patients
with stable CAD without left ventricular dysfunction
(21). This type of study is relevant as undesirable ef-
fects of beta-blockers such as impaired reduction
of central aortic pressure (22), symptomatic brady-
cardia, high-grade atrioventricular block, hypoten-
sion, and depression may contribute to observed
differences in clinical outcomes between patients on
and off beta-blocker therapy. Importantly, both the
REACH registry and the Kaiser Permanente analysis
did not suggest harm from beta-blockade.
Andersson et al. (16) argue that their findings
support a prospective, randomized, controlled trial to
test the prognostic benefit of beta-blockade in
asymptomatic patients with stable CAD. In an ideal
world, that may be true. However, given the excellent
clinical outcomes in this patient group with contem-
porary treatment (23), it will be a major challenge to
attract the resources needed to conduct what would
necessarily be an extremely large trial.
WHAT ARE THE CLINICAL IMPLICATIONS?
The analysis by Andersson et al. (16) strengthens the
view that systematic use of beta-blockers is not
mandated on prognostic grounds for all patients with
stable CAD, especially in the absence of previous MI.
These drugs should be used for symptomatic angina
relief, as recommended in the ACC/AHA (12) and ESC
(13) guidelines. This recommendation will come as
welcome relief for stable CAD patients, the vast ma-
jority of whom are asymptomatic and are prescribed a
plethora of pharmacologic agents, including anti-
platelet therapy, statins, and blockade of the renin-
angiotensin system to improve prognosis. For those
patients with a known history of MI, routine admin-
istration of beta-blockers seems reasonable, although
the benefits of prolonged treatment in the asymp-
tomatic patient without left ventricular dysfunction
remains debatable. While guidelines currently
recommend 3 years of beta-blocker treatment after
presentation with ACS (12), should side effects occur
there is no definitive evidence to insist on continued
treatment. The report by Andersson et al. (16) sup-
ports tailoring treatment decisions for patients with
stable CAD: defining the most parsimonious bespoke
therapeutic regimen, which renders an individual
patient free of symptoms and improves prognosis
with minimal side effects, is particularly important,
to ensure treatment compliance as well as optimize
quality-of-life and clinical outcomes, especially in an
era of constrained healthcare resources.
REPRINT REQUESTS AND CORRESPONDENCE:
Dr. Philippe Gabriel Steg, Hôpital Bichat, Assistance
Publique–Hôpitaux de Paris, 46 rue Henri Huchard,
75018 Paris, France. E-mail: gabriel.steg@bch.aphp.fr.

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KEY WORDS beta-blockers, coronary artery
disease